Trusting your gut can be considered reasonable advice when you feel the creep of indecision. But it may not be the best course of action in the body’s fight against cancer.
New research from Harvard scientists published May 3 has further explored how the gut microbiota—a catch-all term for the microorganisms, including bacteria and fungi, which live in the digestive tract—could be the culprit for why immunotherapy is ineffective in some cancer patients. The scientists outlined the relationship between gut behavior and PD-L2 and repulsive guidance molecule b (RGMb), two molecules that play a role in immune system activation—or lack thereof.
“Our findings offer a critical clue into a complex puzzle and in doing so suggest concrete ways to enhance the potency of cancer immunotherapy and improve patient outcomes,” Joon Seok Park, Ph.D., co-lead author of the new paper, said in a release. “We propose a new approach to overcome the resistance to the current cancer immunotherapies by learning from gut bacteria that help our immune system to fight cancer.”
Researchers working under Harvard Medical School Professors Dennis Kasper, M.D., and Gordon Freeman, Ph.D., seeded microbiota from cancer patients into the colons of mice. The sourced patients had either responded positively or negatively to past immunotherapy treatments. When those mice were then treated with immunotherapy, the response mimicked that of the corresponding adult. Further analysis showed that mice infused with gut cells of patients who responded well to immunotherapy also had low levels of PD-L2 on antigen-presenting cells.
Interestingly, treating gut bacteria with antibiotics did not suddenly improve the mice’s response to immunotherapy, suggesting there was another factor at play. That’s where RGMb comes in. Freeman’s lab had previously investigated the research between RGMb and PD-L2 and so, this time around, researchers treated mice with anti-RGMb antibodies. And bingo, when RGMb was blocked, mice started to produce cancer-killing cells and saw an improvement in health.
The scientists concluded there is a correlation between the amount of gut microbiota and RGMb levels. Specifically, sufficient microbiota levels were associated with lower levels of RGMb and better response to immunotherapies, while depleted microbiota had the reverse impact.
“The interplay between the microbiota and immune cells in the anticancer response just got clearer, and with the identification of RGMb as PD-L2’s molecular accomplice, we have another target for cancer immunotherapy,” Freeman said in a release.
The findings describe a clear opportunity for new therapies that could bolster existing checkpoint inhibitors, specifically small molecules. And the researchers who helped lead this effort seem aware; Freeman is listed as the inventor on a patent owned by the Dana-Farber Cancer Institute for a combination immunotherapy aimed at RGMb and PD-1.